Use of selective estrogen receptor modulator for joint fusion and other repair or healing of connective tissue

ABSTRACT

Methods for facilitating joint immobilization or fusion using selective estrogen receptor modulator (SERM) such as raloxifene are disclosed. The SERM may be administered systemically or locally. In conjunction with SERM, other therapeutic agents such as calcium, vitamin D, bone morphogenetic protein may be administered simultaneously. The method can similarly be applied to facilitate bone repair, bone healing, and connective tissue healing processes in a patient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of copending U.S. patent applicationSer. No. 12/771,752 to Stark filed on Apr. 30, 2010, entitled “Use ofSelective Estrogen Receptor Modulator for Joint Fusion and Other Repairor Healing of Connective Tissue,” incorporated herein by reference.

FIELD OF THE INVENTION

The inventions in general are related to the method of using selectiveestrogen receptor modulators (SERMs) to facilitate joint fusion. Theinventions are further related to methods of using SERMs to facilitatebone repair, bone healing, or connective tissue healing processes ingeneral.

BACKGROUND

Bone is a dynamic biological tissue composed of metabolically activecells that are integrated into a rigid framework. The healing potentialof bone, whether in a fracture or fusion model, is influenced by avariety of biochemical, biomechanical, cellular, hormonal, andpathological mechanisms. A continuously occurring state of bonedeposition, resorption, and remodeling facilitates the healing process.The success of many spine operations depends on the restoration oflong-term spinal stability. Whereas spinal instrumentation devices mayprovide temporary support, a solid osseous union is desired to providelong term stability. The failure of fusion to occur may result in thefatigue and failure of supporting instrumentation and persistence orworsening of symptoms.

Bone metabolism is regulated by a host of hormonal and local factors.Three of the calcitropic hormones that affect bone metabolism areparathyroid hormone, vitamin D, and calcitonin. Bone metabolism is alsoaffected by a series of proteins, or growth factors, released fromplatelets, macrophages, and fibroblasts. These proteins cause healingbone to vascularize, solidify, incorporate, and function mechanically.They can induce mesenchymal-derived cells, such as monocytes andfibroblasts, to migrate, proliferate, and differentiate into bone cells.The proteins that enhance bone healing include the BMPs, insulin-likegrowth factors, transforming growth factors, platelet derived growthfactor, and fibroblast growth factor, among others.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a method for facilitating jointimmobilization or fusion. The method comprises the step of administeringa composition comprising an effective amount of a selective estrogenreceptor modulator (SERM) to a patient who has received animmobilization element interfacing with a joint, to result in jointimmobilization or fusion. In some embodiments, the SERM is administereddirectly to the joint or surrounding tissue to access the immobilizationelement to facilitate joint immobilization or fusion. In otherembodiments, the SERM is administered systemically. Auxiliary agentssuch as calcium, vitamin D, or a combination thereof may be administeredsystemically in addition to the SERM to improve bone healing.Therapeutic agents such as nutritional factors, endocrine factors,growth factors, synthetic or natural anabolic steroids, or a combinationthereof may be administered in addition to the SERM to improve bonehealing. SERM in general includes afimoxifene (4-hydroxytamoxifen),arzoxifene, bazedoxifene, clomifene, femarelle, lasofoxifene,ormeloxifene, tamoxifen, toremifene, analogs or derivatives thereof, ora combination thereof. In one embodiment, the SERM used is raloxifene,analogs or derivatives thereof, or a combination thereof. In someembodiments, a bone morphogenetic protein (BMP), or cellular cytokinemay be administered in addition to the SERM to the joint to access theimmobilization element to facilitate joint immobilization or fusion.Suitable BMP includes BMP-2, BMP-7, or a combination thereof. Suitablecytokine includes one or members of the transforming growth factor beta(TGF-β) super family. In one embodiment, the fusion or immobilizationinvolves fusion of adjacent vertebrae or fusion of the sacroiliac joint.In another embodiment, the fusion or immobilization is fracture unionbetween traumatically induced fractures, stress fractures, or un-unitedfractures. In some embodiments, the composition may be administeredprior to the joint fusion or immobilization procedure.

In a second aspect, the invention relates to a method for facilitating abone repair process in a patient. The method comprises administering aneffective amount of a composition comprising a selective estrogenreceptor modulator (SERM) to the patient to stimulate the bone repairprocess wherein the patient has been provided a bone morphogeneticprotein (BMP) to a location selected for bone repair. In someembodiments, the composition is also administered to the locationselected for bone repair. A suitable patient for the method can be apost-menopausal woman. The bone repair method can be applied to fractureunion between traumatically induced fractures, stress fractures, orun-united fractures. In some embodiments, the composition may beadministered prior to the bone repair procedure.

In a third aspect, the invention relates to a method for the improvementof bone healing. The method comprises administering an effective amountof composition comprising a selective estrogen receptor modulator (SERM)to a patient to improve the bone healing process. In some embodiments,the patient also receives bone graft, bone substitute or otherosteoconductive material. In some embodiments, the bone healing is innon-surgically treated patients.

In a fourth aspect, the invention relates to a method for facilitatinghealing of connective tissue. The method comprises administering acomposition comprising an effective amount of a selective estrogenreceptor modulator (SERM) to a patient to result in improvement inhealing of the connective tissue. The patient may have connective tissueinjury including laceration, contusion, ischemia, anoxia, or avulsion ofthe connective tissue. Additionally, the patient may have congenital,endocrine, or nutritional imbalance related to connective tissue. Insome embodiments, the patient receives soft tissue autograft orallograft. In other embodiments, the patient receives prosthesis,scaffold, or attaching implant to facilitate connective tissuecontinuity. In one embodiment, the connective tissue comprises theintervertebral disc. The connective tissue may comprise tendon,ligament, bone, dysvascular connective tissue, or theirinterrelationships and connections. In one embodiment, the compositionis controllably released from a suture.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic drawing of a simplified scheme of bone healingwith or without exogenous stimulants.

FIG. 2 is a histogram plot of the sacroiliac joint fusion rate of (a)patients who are smokers or non-smokers and (b) male or female patients,with or without post-surgery exogenous BMP.

FIG. 3 is a set of photographs taken from sacroiliac joint fusion orimmobilization in postmenopausal females showing compromisedincorporation.

FIG. 4 is a set of photographs taken from different perspectives of asacroiliac joint fusion or immobilization in a 30 year old male. Theresults obtained for this patient with the absence of raloxifene exhibitless advanced incorporation as compared to the postmenopausal female ofFIG. 5.

FIG. 5 is a set of photographs taken from different perspectives of asacroiliac joint fusion or immobilization in a postmenopausal femaleadministered with raloxifene showing improved incorporation.

FIG. 6 is a set of photographs providing comparative results from twopostmenopausal female patients who had sacroiliac joint fusion orimmobilization surgeries showing (a) improved incorporation for thepatient who received post surgery raloxifene and (b) compromisedincorporation for the patient who did not receive raloxifene.

FIG. 7 is another set of photographs taken following sacroiliac jointfusion or immobilization in two postmenopausal females showing (a)improved incorporation for the patient who received post surgeryraloxifene and (b) compromised incorporation for the patient who did notreceive raloxifene.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

It has been discovered that the administration of a SERM cansignificantly improve bone turnover and metabolic activity, and byanalogy bone healing can be similarly improved through theadministration of a SERM. In many postmenopausal women after bone fusionor immobilization surgery, complications arise when the treated bonedoes not fuse well. Insufficient hormonal levels such as falloff ofestrogen, parathyroid hormone, growth hormone, thyroid hormone, andinsulin have been attributed to the generalized deficiency of the bonehealing response in post menopausal women. While the localadministration of bone morphogenetic proteins has had some success infacilitating bone fusion processes, the combination of BMP with a SERMhas achieved unexpected synergies. While the effectiveness of SERMswould be expected to be particularly pronounced in post menopausalwomen, the usefulness of SERMs for bone fusion and general bone healingcan be expected to extend to all individuals with or without thecombination with BMP. Based on the physiological effects of SERMsgenerally on connective tissue, SERMs may be desirable agents to beadministered generally to promote the healing of connective tissues,such as ligaments, tendons, intevertebral discs, dysvascular tissues,cartilage and other connective tissues in addition to bone, whether ornot associated with bone. Connective tissue healing, used herein, refersto the general recovery of soft tissues, such as ligaments or tendons aswell as bone and cartilage, and includes healing situations that mayinvolve more than one tissue type, such as tendon to bone, or ligamentto bone. Such processes may comprise initiation or acceleration ofcellular differentiation and division, secretion of intracellularmatrix, or other cellular processes such as apoptosis, resorption orvascular ingrowth.

For bone healing procedures, forces that improve the healing process canreduce the rate of failure of these procedures, the need of painmedication, time off from work, and/or the general debility whichcomplicates the recovery. Improving the result of the healing processand/or accelerating the healing, can reduce costs associated withcontinued care of the patient and reduce costs associated with leavesfrom work as well as improve quality of life for the patient. The phrase“bone healing” in general is used herein to refer to the generalrecovery of joint fusion or immobilization, bone grafting, bone healing,bone repairing, or a combination of these processes. In someembodiments, bone healing refers to bone healing with no surgicalintervention. The term “union” used herein refers to bone cellformation, secretion, and organization of functional bone that areachieved in the bone healing process.

In bone loss related disease such as osteoporosis, one of the importantdiagnostic factors is bone mineral density (BMD), a medical termreferring to the amount of bone matter per cubic centimeter of bone. BMDis tightly regulated by a balance between osteoblasts, mononucleatecells that are responsible for bone formation and osteoclasts, a type ofbone cell that removes bone tissue by removing its mineralized matrixand breaking up the organic bone. Stimulation of osteoblasts andinhibition of osteoclasts therefore can help to accelerate bone turnoverand/or increase BMD and subsequently prevent or even reverse bone loss.SERMs such as raloxifene are believed to reduce osteoclast number andosteoclast-mediated resorption and also induce osteoblast proliferationas disclosed by Cosman et al., in Current Medical Evidence, Vol. 2,Issue 5, entitled “Clinical and Mechanistic Insights into Novel Agentsin Development for Osteoporosis”, incorporated herein by reference.Cosman in fact classified raloxifene under the category ofanti-resorptive or anti-catabolic agents as oppose to anabolic agentssuch as parathyroid hormone, the other class of osteoporosis drugs.

In bone healing/fusion related processes however, in addition to boneformation, reorganization and revascularization of the bone andconnective tissues are believed to be important factors. A certaindegree of bone resorption therefore is believed to be important to allowthe reorganization and revascularization of the bone and connectivetissues to occur. As discussed herein, in addition to stimulating boneformation, SERMs appear to facilitate the bone reorganization andrevascularization processes, thus the healing/fusion of the bone. Thus,it is demonstrated herein that SERMs can also contribute to bonehealing, facilitating bone fusion and other connective tissue healingand tissue maturation processes, whether or not the other connectivetissue is associated with bone.

In addition to repairs of broken bones and other bone repair processes,bone fusion can be used to alleviate pain for certain joints. Forexample, fusion of vertebrae can be useful for reducing back pain. Also,recently fusion of the sacroiliac joint has been found to be effectiveat reducing lower back pain that has been non-responsive to other formsof treatment. See, U.S. Pat. No. 7,648,509 to Stark, entitled“Sacroiliac Joint Immobilization,” incorporated herein by reference (the'509 patent). The sacroiliac joint is not generally amenable to jointreplacement.

As described in the '509 patent exogenous BMP has been used in theperformance of sacroiliac joint fusion procedures. Also, recombinantexogenous BMP has US-FDA approval for use in certain spinal fusionprocedures. However, in some individuals, the fusion process with orwithout BMP has been found to be deficient. The deficiencies of thefusion process for sacroiliac joint fusions were found to beparticularly prevalent in postmenopausal women. It was discovered thatthe administration of SERMs resulted in significant improvement in thejoint fusion in postmenopausal women and based on the superior fusionresults in postmenopausal women relative to other individuals, itfollows that SERMs can be useful in other individuals or patient groupsto improve bone fusion and bone healing results.

Parathyroid hormone increases the flow of calcium into the calcium pooland maintains the body's extracellular calcium levels at a relativelyconstant level. This hormone can induce cytoskeletal changes inosteoblasts. Vitamin D stimulates intestinal and renal calcium-bindingproteins and facilitates active calcium transport. Calcitonin issecreted by the parafollicular cells of the thyroid gland in response toan acutely rising plasma calcium level. Calcitonin serves to inhibitcalcium-dependent cellular metabolic activity.

Bone morphogenetic proteins induce mesenchymal cells to differentiateinto bone cells. Although typically present in only minute quantities inthe body, several BMPs have been synthesized using recombinant DNAtechnology and have undergone clinical trials to assess their potentialto facilitate bone fusion in humans. Other proteins influence bonehealing in different ways. Transforming growth factor and relatedchemicals regulate angiogenesis, bone formation, extracellular matrixsynthesis, and controls cell-mediated activities. Osteonectin,fibronectin, osteonectin, and osteocalcin promote cell attachment,facilitate cell migration, and activate cells.

The hormonal and local factors as well as growth factors can besupplemented in patients. Additionally, small molecule medication can beused to treat bone related disorders. For instance, selective estrogenreceptor modulators (SERMs) are used to treat osteoporosis most notablyin post menopausal women patients. SERMs are drugs that activate orinhibit the estrogen receptors on different tissues. SERMs can act likeestrogen in the desirable ways such as stabilizing bone mass, improvinglipid profile, reducing hot flashes, but may not act like estrogen inundesirable ways such as causing breast cancer or stimulating theendometrium. If appropriately chosen, the SERM can be particularlydesirable to exploit for other healing possibilities.

The bone healing process in general is demonstrated to be facilitated bythe use of selective estrogen receptor modulator (SERM) such asraloxifene. In particular, the combination of a SERM with exogenous BMPsuch as BMP-2 has yielded excellent fusion of sacroiliac joints forpostmenopausal women. Nutritional supplements such as vitamin D andcalcium, endocrine factors, growth factors, and synthetic or naturalanabolic steroids alone or combined can be used in conjunction with SERMand/or BMP-2 to facilitate the healing process.

In some embodiments, a SERM, such as raloxifene, can be administeredlocally or systemically. For example, for systemic administration, theSERM can be ingested at appropriate intervals orally, such as in pillform. In additional or alternative embodiments, a composition containingan effective amount of a SERM can be administered directly to or aroundthe site where bone healing is expected to occur. Local delivery of aSERM may be particularly desirable for some patients in which systemicdelivery may be undesirable. In embodiments where an immobilizationelement is implanted to fuse bone structures, a SERM containingcomposition can be pre-applied to the immobilization element or the SERMcan be independently delivered at the site. The term “immobilizationelement” used herein refers to bone graft, wedge, nail, bone screw, orany mechanical element that can be placed into or near a joint tofacilitate bone stabilization or fusion. Similarly, bone healingelements can comprise joint prostheses, internal fixators, pins, clampsor other mechanical elements that can be used to facilitate bone healingor stabilization. In some embodiments, a SERM containing composition canbe pre-applied to a prosthesis, such as a joint replacement orthosis, ascaffold or attaching implant, such as associated with an orthopedicrepair, a soft tissue autograft, which involves re-location of a portionof a patient's connective tissue, a soft tissue allograft, whichinvolves transplant tissue from a compatible donor or combinationsthereof or the like. For joint fusions or general bone healing, a bonegraft, bone substitute or other osteoconductive material can be used. Anosteoconductive material provides a scaffolding of bone like materialfor bone in-growth. Bone graft or bone substitute materials include, forexample, bone powder, bone segments, hydroxyapatite, tricalciumphosphate, other synthetic bone-like materials or the like orcombinations thereof.

For sustained delivery, a SERM can be embedded in a controlled releasevehicle such as a hydrogel. In some embodiments, a SERM can beadministered in the form of an implant and a reservoir. Alternatively, aSERM can be administered systemically, topically, intravenously,intramuscularly, orally, rectally, with a patch, or locally. Generally,a SERM can be administered prior to, during, and/or after a bonetreatment procedure, sometime for an extended period of time such as 3months or more. Long term systemic oral delivery of raloxifene at adosage of 60 mg/day for example has been routinely administered topostmenopausal women for treatment of osteoporosis. Side effectsinclude, for example, hot flashes, leg cramps and blood clots areobserved in some patients. Raloxifene has also been administered orallyto male patients at 60 mg/day to treat prostate cancer in U.S. Pat. No.7,425,565 to Agus et al. entitled “Use of Benzothiophenes to Treat andPrevent Prostate Cancer”, incorporated herein by reference showingsimilar side effects as in female patients, although co-administrationof estrogen inhibitor is recommended. Raloxifene thus appears to be safein both male and female patients.

The treatment options described herein can be used to improve fusion ofvertebrae, sacroiliac joint fusion, fracture union between traumaticallyinduced fractures, stress fractures, or un-united fractures, bonerepair, and bone healing in general. With appropriate adaptation ofadministration route and timing, the treatment can be applied to bothfemale and male patients. The treatment may be particularly useful forpost menopausal female patients. In more generalized applications, thecomposition and methods described herein can be use to facilitate thehealing of connective tissue in general. Patients with connective tissueinjuries such as laceration, contusion, ischemia, anoxia, or avulsionmay be treated with SERM containing compositions to facilitate thehealing processes in general.

Selective Estrogen Receptor Modulator (SERM) in Connective TissueHealing

As described herein, it has been discovered that SERMs are effective tofacilitate healing of connective tissue, in particular bone. The healingcan be associated with bone fusion. Selective Estrogen ReceptorModulators (SERMs) are a class of compounds that selectively act onestrogen receptors. A characteristic that distinguishes these substancesfrom pure receptor agonists and antagonists is that their action isdifferent in various tissues, thereby granting the possibility toselectively inhibit or stimulate estrogen-like action in varioustissues. Phytoserms for example are considered SERMs from a botanicalsource. Other members of the SERM family include, for example,afimoxifene (4-hydroxytamoxifen), arzoxifene, idoxifene, bazedoxifene,clomifene, femarelle, lasofoxifene, ormeloxifene, tamoxifen, raloxifene,toremifene, combinations thereof and salts thereof. SERMs and medicinalformulations of SERMs are discussed generally in published U.S. patentapplication 2008/0175905A to Liu et al., entitled “Estrogen/SERM andEstrogen/Progestin Bi-Layer Tablets,” and in U.S. Pat. No. 6,894,064 toArbuthnot et al., entitled “Benzothiophene, Formulations ContainingSame, and Methods”, both incorporated herein by reference. In general,SERMs as used herein refer to known or future developed or discoveredSERMs, as recognized generally in the art. Additionally, analogs orderivatives of SERMs can be similarly used. For example analogs orderivatives of raloxifene disclosed in U.S. Pat. No. 4,133,814 to Joneset al., entitled “2-Phenyl-3-aroylbenzothiophenes Useful asAnti-fertility Agents,” U.S. Pat. No. 4,380,635 to Peters entitled“Synthesis of Acylated Benzothiophenes,” and U.S. Pat. No. 4,418,068 toJones entitled “Anti-estrogenic and Anti-androgenic Benzothiophenes,”all incorporated herein by reference, can be selectively used based onactivity and choice of method of delivery. Analogs refer to chemicallysimilar compositions that can be recognized by a person of ordinaryskill in the art to have an expected similar efficacy based on similarchemical structure, and derivatives refer to chemical derivatives thatcan be expected by a person of ordinary skill in the art to have similaractivity based on the particular derivation of the original composition.

Historically, SERMs were referred to as anti-estrogens, but this termhas fallen into disfavor due to inaccuracy of the more complexinteractions now associated with SERMs. Depending on pattern of action,SERMs can be used in treatment of diseases in various tissues. Forexample, clomifene is used in anovulation, femarelle is used formanaging menopause symptoms and maintaining bone health, ormeloxifene isused for contraception, raloxifene is used for the treatment andprevention of osteoporosis in postmenopausal women, and tamoxifen andtoremifene are used for treatment related to breast cancer. Some SERMsmay be suitable replacements for hormone replacement therapy (HRT) insome women. Some of the above agents still have significant side-effectswhich contraindicate widespread long term use.

In general, SERMs span a spectrum of activity ranging from full agonists(agonistic in all tissues) such as the natural endogenous hormoneestrogen, mixed agonists/antagonists (agonistic in some tissues whileantagonistic in others) such as tamoxifen, and pure antagonists(antagonistic in all tissues) such as fulvestrant (ICI-182780). Themechanism of mixed agonist/antagonist activities may differ depending onthe chemical structure of the SERM. For example, the SERM tamoxifen actsas an antagonist in breast and conversely an agonist in uterus. Theconcentration of steroid receptor co-activator 1 (SRC-1; NCOA1) ishigher in uterus than in breast, therefore SERMs such as tamoxifen aremore agonistic in uterus than in breast. In contrast, raloxifene behavesas an antagonist in both tissues. It appears that raloxifene morestrongly recruits co-repressor proteins and consequently is still anantagonist in the uterus despite the higher concentration ofco-activators relative to co-repressors.

SERMs have effects on various tissues. Bone turnover and postmenopausalosteoporosis respond favorably to most SERMs. In breast, all SERMsdecrease breast cancer risk, and tamoxifen is mainly used for itsability to inhibit growth in estrogen receptor-positive breast cancer.Cholesterol and triglycerides levels respond in general favorably toSERMs. The risk of deep venous thrombosis however may be elevated in atleast some SERMs. Hot flashes are increased by some SERMs. Clomifene isknown to act on pituitary gland by blocking estrogen action leading toan increase of follicle-stimulating hormone. In uterus, althoughtamoxifen may increase endometrial carcinoma risk, raloxifene andfemarelle do not seem to have this side effect.

Raloxifene(6-hydroxy-2-(4-hydroxyphenye-benzothiophen-3-yl)]-[4-(2-(1-piperidyl)ethoxy)phenyl]-methanone) is an alternative to traditional hormonereplacement therapy for the prevention and treatment of osteoporosis inselected postmenopausal women. The recommended dosage is 60 mg/dayorally, and the drug is sold under the trade name Evista™ by Eli Lily.Raloxifene is a selective estrogen receptor modulator (SERM) that inexperimental animals acts as an estrogen receptor antagonist in breastand endometrium but as an estrogen receptor agonist in the skeletal andcardiovascular systems. Lufkin et al in Journal of Bone and MineralResearch, 1998:13:1747-1754 entitled: “Treatment of EstablishedPostmenopausal Osteoporosis with Raloxifene: A Randomized Trial”,incorporated herein by reference, demonstrated among the raloxifenetreated groups and control there were no differences among groups in theoccurrence of uterine bleeding, thrombophlebitis, breast abnormalities,or increased endometrial thickness as assessed by ultrasonography.Lufkin et al concluded that that raloxifene therapy for osteoporosis iswell tolerated, reduces serum lipids, and does not stimulate the uterusor breasts. Additionally, it was concluded that raloxifene hasbeneficial effects for reduction of bone mass although the beneficialeffects were reported to be of a smaller magnitude than have beenreported with estrogen therapy.

Preswood et al compared the effect of estrogen with raloxifene in theJournal of Clinical Endocrinology & Metabolism Vol. 85, No. 6,2197-2202, entitled: “A comparison of the effects of raloxifene andestrogen on bone in postmenopausal women”, incorporated herein byreference. According to Preswood, raloxifene did not decrease activationfrequency, bone formation rate or bone volume as did estrogen. Besidebeing known to have no stimulatory effects on breast and uterus, Snyderet al showed raloxifene may also reduce the incidence of breast cancerand has a positive effect on serum lipids in American Journal ofHealth-System Pharmacy, Vol. 57, Issue 18, 1669-1675, entitled:“Raloxifene hydrochloride”, incorporated herein by reference.

Raloxifene also appears to be superior to other agents such asalendonate that work through the mechanism of inhibiting bone resorbingcells, the osteoclast. Sambrook et al disclosed in Journal of InternalMedicine. 255(4):503-511, entitled: “Alendonate produces greater effectsthan raloxifene on bone density and bone turnover in postmenopausalwomen with low bone density: results of EFFECT (Efficacy of FOSAMAX®versus EVISTA® Comparison Trial) International 1”, incorporated hereinby reference, that alendonate results in high bone density and lowerbone turnover comparing to raloxifene. The result of decreasedreabsorbtion is increased bone mass although such bone mass may not benormally organized due to the decrease in bone resorption.

Raloxiphene is believed to be useful for potentiating endogenous BMP-2.U.S. Patent Application No. 2005/0271637 to Bodine et al. (the Bodineapplication) entitled “BMP-2 estrogen responsive element and methods ofusing the same” incorporated herein by reference, points out that thepotentiating effects of estrogen are primarily on the α-estrogenreceptor, where the potentiating effect of raloxifene also is believedto occur. Although tamoxiphene has a similar but smaller effect, it alsohas general systemic effects such as on breast and uterus. The desirableselectivity of raloxifene makes it a medication with improvedspecificity. The Bodine application showed direct measurable effect ofestrogen on endogenous BMP-2 secretion, presumably through its directeffect on related mRNA. The effect of raloxifene is shown to be similar.

It has been found that SERMs are also effective for facilitating bonefusion through its effect on natural bone and connective tissueprocesses, and based on these results, SERMs can be effective tofacilitating the healing of connective tissue generally. Furthermore, ithas been found that SERMs have a synergistic efficacy in combinationwith exogenous BMP. In general, SERMs, therefore, can be used for anypatient, although the use of SERMs with postmenopausal women can beparticularly desirous since deficiencies of natural hormones for bonehealing complicate these processes in this group. SERMs can beadministered systemically or through local administration near thedesired location for connective tissue healing. Raloxifene can be adesirable SERM for connective tissue healing due to its believed lowlevels of certain undesirable side effects.

Therefore, raloxifene can be used together with exogenous BMP-2, such asInfuse™ from Medtronic. Raloxifene can be useful for potentiatingexogenously applied BMP-2, such as Infuse™ from Medtronic, forconnective tissue healing, bone fusion or normal fracture situations,where increased bone turnover is believed to be important. Othermembers, or their derivatives, or their analogs, in the family of SERMmay also be used to facilitate bone healing or other connective tissuehealing processes.

In some embodiments, the bone healing process is facilitated by the useof selective estrogen receptor modulator (SERM) such as raloxifene incombination with exogenous BMP-2. Nutritional supplements, such asvitamin D and calcium, endocrine factors, growth factors, and syntheticor natural anabolic steroids can be used in conjunction with SERMs, suchas raloxifene, and optional also with BMP, such as BMP-2. Many patientsinvolved in bone related surgical procedures may be nutritionallydeficient. The most obvious and common deficiency is vitamin D. Othercommon micronutrients like silicon or zinc may also play a role. VitaminD in particular can be used in conjunction with calcium to facilitatethe bone healing processes.

Sacroiliac Joint Fusion, Vertebrae Fusion, Bone Repair, Bone Healing andBMP

It has been discovered that bone fusion can be facilitated through theadministration of SERMs, in particular raloxifene. The healing responseinvolved in the fusing of joints involves many physiologicalsimilarities with other bone healing responses. Bone healing or growthis believed to be influence by cell differentiation and vascularizationas well as reorganization of the bone tissue. Beyond simple celldivision and differentiation, vascularization and organization of thebone tissue are essential to achieve healed bone. In bone graft andjoint fusion surgeries, for example, after surgery at least part of thebone graft or implant remains avascular and unorganized in manypatients. Stimulatory agents to facilitate the incorporation of boneimplants have been used to help facilitate the bone healing processes.U.S. Patent Application No. 2009/0024174 to Stark et al, entitled: “Bonescrews and particular applications to sacroiliac joint fusion”,incorporated herein by reference, for example disclosed the use of bonemorphogenetic protein (BMP) during sacroiliac joint fusion surgery tofacilitate recovery.

Joint fusion can comprise the insertion of an immobilization elementinto the joint. Suitable immobilization elements can include, forexample, shims, wedges, nails, screws, cages, and the like. Anyreasonable element can be used. In some embodiments, the immobilizationelement may be hollow and may be fenestrated to allow bone growththrough the wall of the element and into the element. For theseembodiments, a therapeutic composition can be placed into the hollowinterior of the element for local delivery of the therapeuticcomposition. Generally, the immobilization element can be constructedfrom any suitable biocompatible material, such as metals, polymers,ceramic or bone material, or combinations thereof. Suitable metalsinclude, for example stainless steel and/or titanium. Suitable ceramicsor bone material include, for example, hydroxyapatite and/or powderedbone. Immobilization elements, such as for sacroiliac joint fusion, aredescribed further in U.S. Pat. No. 7,648,509 to Stark, entitled“Sacroiliac Joint Immobilization,” incorporated herein by reference.

Bone morphogenetic proteins (BMPs) are a group of growth factors andcytokines known for their ability to induce the formation of bone andcartilage. Originally, seven such proteins were discovered, of which sixincluding BMP-2 through BMP-7 belong to the transforming growth factorbeta (TGF-β) superfamily of proteins. BMP-1 is a metalloprotease.Thirteen more BMPs have since been discovered, bringing the total ofknown BMPs to twenty. BMPs can now be produced using recombinant DNAtechnology and have found applications in many disciplines of medicineand dentistry. Orthopedic surgery and oral surgery in particular havebenefited greatly from commercially available BMP formulations. Aformulation containing natural BMPs for example is available in oralform under the commercial name Ostinol™. It is being marketed as asupplement for bone and joint health by alternative health carepractitioners. In regenerative medicine, BMPs are delivered to the siteof the fracture, being incorporated into the bone implant, which is thenreleased gradually to facilitate bone formation. The stimulus suppliedby BMPs however, can be localized, and it may be useful to sustain theeffects for some weeks to achieve measurable improvement. Currently, twoBMP products have been approved by the Food and Drug Administration(FDA) for clinical applications including fractures of long bones andintervertebral disk regeneration. The two products are Infuse™ BMP-2(Medtronic) and OP-1 BMP-7 (Stryker Biotech) where the exogenous BMPsare delivered in a purified collagen matrix, which is then implanted inthe site of the fracture. BMP-2 has also been used for spinal fusionprocedures and sacroiliac joint fusion procedures. The results ofsacroiliac joint fusion procedures with BMP are summarized in theexample below.

Referring to FIG. 1, a simplified scheme of bone healing with or withoutexogenous stimulation agent is shown. First, stem cells differentiateinto osteoblasts, which secrete endogenous bone morphogenetic protein 2(BMP-2). BMP-2 in turn induces osteoblasts differentiation intoosteocytes, causes angiogenesis, and stimulates other processesnecessary for bone healing. Martine et al. disclosed in EndocrinologyVol. 143, No. 4 1545-1553, entitled “Growth factors-cytokines-oncogenes”incorporated herein by reference, that BMP stimulates angiogenesisthrough the production of vascular endothelial growth factor (VEGF) byosteoblasts and the VEGF thus produced however is not involved inosteoblasts differentiation. In addition to VEGF, other bone anabolicagent may also be involved in the bone formation process. Kawaguchi etal disclosed in the Journal of Clinical Endocrinology & Metabolism Vol.86, No. 2 875-880 entitled: “Acceleration of fracture healing innonhuman primates by fibroblast growth factor-2” incorporated herein byreference, that fibroblast growth factor-2 (FGF-2) accelerates fracturehealing and prevents nonunion in primates, and therefore is a likelypotent bone anabolic agent for clinical use.

Given the important stimulatory role of the endogenous BMP-2, exogenousBMP-2 is used in surgical procedures to help facilitate bone healing. Ingeneral, the exogenous BMP-2 can be administered systemically forexample in oral form or locally. The FDA approved BMP products are soldin a form for local delivery. In general, an appropriate BMP can beselected to facilitate bone fusion, bone healing and the healing ofother connective tissue, such as cartilage. As used herein, BMP refersto natural purified proteins, synthetic proteins, and effectivederivatives thereof as well as nucleic acid coding for the BMP witheffective control elements that provide for in vivo expression. BMP isdescribed further in published U.S. patent application 2009/0202638A toHidaka et al., entitled “BMP Gene and Fusion Protein,” incorporatedherein by reference. As indicated in the examples below, exogenous BMP-2may not be sufficient enough to achieve a desired level of bone fusionin some patients. Administration of raloxifene (or a similar selectiveestrogen receptor modulator) has been demonstrated to improve bonefusion results in patients as discussed in the examples below.

Selective Estrogen Receptor Modulator (SERM) in Tissue Healing

Similar to bone, other connective tissues including, for example, skin,vascular tissues, ligaments, cartilage and tendon also contain receptorsthat respond to estrogen as well as various exogenous regulatory factorsthat are agonist or antagonist with respect to estrogen receptors. Themethods disclosed herein to facilitate bone healing therefore can besimilarly applied to facilitate the connective tissue related healing ingeneral as a result of interactions with similar receptors. Whether ornot local or systemic delivery of the SERM is appropriate may beinfluenced by the particular condition being addressed.

For example, Irie et al. in “Effect of Selective Estrogen ReceptorModulator/Raloxifene Analogue on Proliferation and Collagen Metabolismof Tendon Fibroblast,” 56^(th) Annual Meeting of the OrthopaedicResearch Society, Poster No. 1117, has shown regulatory effect ofestrogen and raloxifene analogue on collagen synthesis and degradationin connective tissue besides bone. Kato et al., in “Raloxifene inhibitsTNF-α induced apoptosis via INK-BAD signaling pathway in osteoblasticcells,” 56^(th) Annual Meeting of the Orthopaedic Research Society,Poster No. 525, has shown raloxifene has anti-apoptotic effect toprotect osteoblastic cells. Hettrich et al. in “The Effect ofRecombinant Human Parathyroid Hormone (rhPTI-1) on the Healing of Tendonto Bone in a Rat Model,” 56^(th) Annual Meeting of the OrthopaedicResearch Society, Poster No. 1105, reported rhPTH improved tendon repairand tendon qualities. All four references are incorporated herein byreference. The method of using SERMs to facilitate tissue healing may beused in patient having connective tissue injury including laceration,contusion, ischemia, anoxia, or avulsion of the connective tissue. Someof the patients who have congenital, endocrine, or nutritional imbalancerelated to connective tissue may especially benefit from treatmentsusing SERMs. For these applications, the combination with a BMP may alsobe effective in a synergistic fashion.

Administration of the SERM and Optional BMP or Other Therapeutic Agent

The therapeutic agents discussed herein may be delivered systemically,e.g., via oral route, locally via direct administration into the site ofsurgery or a combination thereof. Auxiliary delivery agent such ashydrogel for controlled released maybe used to help achieve desiredadministration effect. The SERM may be administered systemically,topically (for example as a patch), intravenously, intramuscularly,orally, rectally, or locally within the patient such as at the site of aprocedure. For example, the SERM can be administered directly to thejoint or surrounding tissue to access the immobilization element tofacilitate joint immobilization or fusion. The SERM may be administeredfrom an internal or an external reservoir. In some embodiments, the SERMcontaining composition may be pre-applied to an immobilization elementor a reservoir for administration within the patient.

A BMP can be delivered in conjunction with the SERM, and the BMP may ormay not be delivered in an analogous fashion as the SERM. In general,the BMP may be delivered locally or systemically. Desirable results havebeen obtained with local delivery of BMP for joint fusion, and sideeffects associated with local delivery have not been generallydeleterious on the patients. As noted above, BMP-2 and BMP-7 areavailable commercially for local delivery into a patient. The commercialBMP-2 is a version derived from recombinant nucleic acid techniques. Inalternative or additional embodiments, a BMP can be administeredsystemically based on an appropriate formulation. Other supplementalagents described above can be administered along with or independentlyfrom a SERM, a BMP or a combination thereof for local delivery orsystemic delivery.

In summary, a therapeutic composition of relevance herein can comprise aSERM, an optional BMP, an optional supplemental therapeutic agent or acombination thereof. In general, a therapeutic composition can comprisea SERM, and the same composition or additional compositions can comprisean optional BMP and/or an optional supplemental therapeutic agent. Eachtherapeutic composition can be independently formulated as either anagent for localized delivery or for systemic delivery, and fortime-dependent delivery by certain preferred timings and routes.Significant versatility can be obtained through the selective deliveryof the agents, although other conveniences can be achieved throughsimultaneous delivery.

Systemic doses of a therapeutic agent generally can be repeated for aperiod of time. For example, doses can be administered multiple times ina day, once a day or less frequently. The frequency may depend on therate of metabolism or otherwise removal from the patient's body. Thetotal treatment period can be select to account for the healing orfusing process. For example, the treatment can be continued in someembodiments for a period of three months, for a period of one month,intermediate period, longer periods or shorter periods as appropriate.Local delivery of a therapeutic agent generally is performed once,although in principle local delivery of a therapeutic agent near thesite of connective tissue healing can be repeated. The local delivery ofthe therapeutic agent can involve a vehicle that provides for gradual ortimed release of the therapeutic agent to keep the local dose of thetherapeutic agent near desired values.

For local delivery, the dosage amount of a SERM composition administeredto a patient may be determined by physical and physiological factorssuch as body weight, severity of condition, previous or concurrenttherapeutic interventions, individualized for the patient and by theroute of administration. The practitioner responsible for administrationcan, in any event, determine the concentration of active ingredient(s)in a composition and appropriate dose(s) for the individual subject.

In certain embodiments, pharmaceutically acceptable compositions maycomprise, for example, at least about 0.1% of a SERM compound. In otherembodiments, the active compound may comprise between about 2% to about75% of the weight of the unit, or between about 25% to about 60%, forexample, and any range derivable therein. In other non-limiting examplesfor local delivery, a local dose may also comprise the equivalent of atleast about 1 microgram/kg-body weight, about 5 microgram/kg-body weightto about 1000 mg/kg-body weight, about 25 microgram/kg/body weight toabout 750 mg/kg-body weight, about 100 microgram/kg-body weight to about500 mg/kg-body weight, about 500 microgram/kg-body weight to about 250mg/kg-body weight, and in further embodiments about 1 milligram/kg-bodyweight to about 100 milligram/kg-body weight. For systemic delivery insome embodiments, daily doses can be in the range of about 1.0mg/kg-body weight to about 500 mg/kg-body weight, in further embodimentsfrom about 2.0 mg/kg-body weight to about 300 mg/kg-body weight and inother embodiment from about 5 mg/kg-body weight to about 250 mg/kg-bodyweight. Systemic doses can be continued for an effective period of timeduring the healing process, such as from about 1 day to about 12 months,or longer depending on the goal and patient response. In some cases theSERM may be continued for years. In further embodiments from about 4days to about 9 months, and in additional embodiments from about 7 daysto about 6 months. A person of ordinary skill in the art will recognizethat additional ranges within the explicit ranges above are contemplatedand are within the present disclosure.

The administration of the SERM may occur before, after or simultaneouslywith the BMP agent and may be to a single targeted site or separatesites. Local delivery of the therapeutic composition of BMP or SERM andother pharmacologic or endocrine components involves delivery of aquantity of the therapeutic composition in the vicinity of the bone orother connective tissue that is targeted for healing, fusion or thelike. The therapeutic agent associated with the therapeutic compositioncan be delivered over time. While some of the therapeutic agent canmigrate from the treatment site, the local delivery can involve anoverall reduced dose such that potential side effects arecorrespondingly reduced. Thus, SERMs can be delivered to individuals tofacilitate connective tissue healing with reduced risks of undesiredeffects.

Local delivery can be effectuated with an appropriate tool to providefor the delivery. For example, the therapeutic composition can be placedinto an immobilization element or coated onto an immobilization element.Alternatively or additionally, the therapeutic composition can beseparately placed at the site of the procedure using, for example, asyringe, a spatula, forceps or other suitable tool. The selection of thetool can be based on the nature of the therapeutic composition. Ingeneral, the therapeutic composition can be, for example, a viscousliquid, e.g., a suspension, a powder, a gel, a solid or other suitableform or combination of forms. In general, the therapeutic composition isselected so that it does not migrate far from the site where thecomposition is placed. In some embodiments, the therapeutic agent can begradually released. For example, the therapeutic agent can be associatedwith a resorbable medium, such as a collagen material, a bone material,a biodegradable polymer, suture, combinations thereof or the like.

The dose of BMP may be highly selective, based on methods ofadministration and the particular procedure on the patient. EndogenousBMP is produced by many cells in the maturing connective tissuesituation, including osteoblasts, mesenchymal cells and chondrocytes. Inan untreated natural situation of healing, BMP can be delivered to beconcentrated in the area, or be continually released, to have its localeffects dominate. In a normal untreated fracture, the amount ofendogenous BMP is very low. Typical dosages used with the MedtronicInfuse™ system, administered on a collagen sponge depot, for example canrange from approximately one milligram rhBMP-2 for a cervical fusion to12 mg or more for complex or large spinal fusions. The dose appropriatewith cotreatment with a SERM, endocrine, or nutritional factors may bemore or less, depending on type of BMP used, timing of release, localphysiology, age of patient, and the specific combination of growth,stimulation or nutritional factors. In some embodiments, BMP doses canbe in the range of about 0.1 mg to about 60 mg, in further embodimentsfrom about 0.5 mg to about 30 mg and in other embodiment from about 1.2mg to about 10 mg. The time release composition can comprise anappropriate concentration, and the commercial product is believed tocomprise about 1.5 mg/mL concentration in a liquid that is absorbed intoa collagen matrix. A person of ordinary skill in the art will recognizethat additional ranges within the explicit ranges above are contemplatedand are within the present disclosure. The BMP generally is graduallyreleased.

For local delivery, a therapeutic composition comprising a SERM or othertherapeutic agent may be formulated in a polymer coating that affordscontrolled release through the healing period following bone or tissuerelated trauma or surgery. In some embodiments SERM may be encapsulatedin polymeric nanoparticles for sustained control release. Alternatively,hydrogel such as collagen can be used. For example, commerciallyavailable BMP such as Infuse™ is dissolved in water which is then soakedup in a collagen sponge for controlled release and sustained delivery.An examplatory osteogenic collagen sponge composition is disclosed inU.S. Pat. No. 7,563,455 to McKay et al., entitled “Highly-mineralizedosteogenic sponge compositions, and uses thereof”, incorporated hereinby reference. Polymeric nanoparticles encapsulated SERM can be suspendedin water or biocompatible buffer to be soaked up together with BMP intothe collagen sponge for controlled and sustained delivery.

The SERM compounds may be provided as pharmaceutically acceptable salts,or in pharmaceutically acceptable diluents or excipients.Pharmaceutically acceptable salts of the compounds described herein maybe synthesized according to methods known to those skilled in this art,see, for example Pharmaceutical Salts: Properties, Selection, and Use,P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor) June 2002.Generally, such salts are prepared by reactions of the free base formsof these compounds with a stoichiometric amount of the appropriate acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile generally are suitable. Lists of someappropriate salts are found, for example, in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985.

For systemic delivery, the therapeutic composition can be formulated,for example, for injection, intravenous delivery, oral delivery,transdermal patches or other suitable delivery technique. Systemicdelivery involves the administration of the composition for circulationthrough the patient's body. In some embodiments, the therapeuticcomposition, which may comprise a SERM, can be administered orally insolid dosage forms, such as capsules, tablets, and powders, or in liquiddosage forms, such as elixirs, syrups, and suspensions. The SERM canalso be administered parenterally, in sterile liquid or in depotadministration dosage forms.

The SERM compounds may be administered in oral dosage forms that caninclude, for example, tablets, capsules, pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Oral ingestionforms of some serves are presently commercially available. Further, thecompounds may be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form. An effectiveamount of the SERM compounds described herein can be administered in amixture with suitable pharmaceutical diluents, excipients, extenders, orcarriers (termed herein as a pharmaceutically acceptable carrier, or acarrier) suitably selected with respect to the intended form ofadministration and as consistent with conventional pharmaceuticalpractices. In some embodiments, the deliverable compound can be in aform suitable for oral, rectal, topical, intravenous injection orparenteral administration. Suitable carriers combined with thetherapeutic agents can comprise solids or liquids, and the type ofcarrier can be chosen based on the type of administration being used.The effective amount can be determined as an amount that provides somerelief from the symptoms to be alleviated.

Techniques and compositions for making dosage forms useful in thepresent invention are described, for example, in the followingreferences: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al.,1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition(1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack PublishingCompany, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.).

Suitable binders, lubricants, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents may beincluded as suitable components for therapeutic compositions, e.g., forpills. For instance, an active drug component, i.e. therapeuticagent(s), can be combined with an oral, non-toxic, pharmaceuticallyacceptable, inert carrier such as lactose, gelatin, agar, starch,sucrose, glucose, methyl cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, mannitol, sorbitol and the like forappropriate embodiments.

Suitable binders can include, for example, starch, gelatin, naturalsugars such as glucose or beta-lactose, corn sweeteners, natural andsynthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms can include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators can include, for example, starch,methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds may also be coupled to polymers as targetable drugcarriers or as a prodrug. Suitable biodegradable polymers useful inachieving controlled release of a drug include, for example, polylacticacid, polyglycolic acid, copolymers of polylactic and polyglycolic acid,caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacylates, and hydrogels, preferablycovalently crosslinked hydrogels. In some embodiment, the compositiondisclosed herein can be embedded in biodegradable sutures for controlledrelease to facilitate healing. The suture can be placed at or near ajoint for fusion or other connective tissue for appropriate treatment.

Capsules may contain the SERM and/or other therapeutic agent describedherein, and powdered carriers, such as lactose, starch, cellulosederivatives, magnesium stearate, stearic acid, and the like. Similarly,such diluents can be used to make compressed tablets. Both tablets andcapsules can be manufactured as immediate release products or assustained release products to provide for continuous or long-termrelease of the active compounds. The deliverable form of the SERM can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

For oral administration as a liquid, the drug components may be combinedwith any oral, non-toxic, pharmaceutically acceptable inert carrier suchas ethanol, glycerol, water, and the like. Example liquid forms include,for example, solutions or suspensions in water, pharmaceuticallyacceptable fats and oils, edible alcohols or other non-toxic organicsolvents, including esters, emulsions, syrups or elixirs, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules and effervescent preparations reconstituted from effervescentgranules. Liquid dosage forms may contain, for example, suitablesolvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring andflavoring, as needed. In general, water, suitable oil, saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, buffer substances. Antioxidizingagents such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or combined, are suitable stabilizing agents. Also used arecitric acid and its salts and sodium EDTA. In addition, parenteralsolutions can contain preservatives, such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceuticalcarriers are described in Remington's Pharmaceutical Sciences, MackPublishing Company, a standard reference text in this field.

The SERM described herein may also be administered in intranasal formvia use of suitable intranasal vehicles, or via transdermal routes,using those forms of transdermal skin patches known to those skilled inthese arts. To be administered in the form of a transdermal deliverysystem, the dosage administration can be effectively continuous for atleast stretches of time rather than intermittent throughout the dosageregimen. Parenteral and intravenous forms may also include minerals andother materials to make them compatible with the type of injection ordelivery system chosen.

The SERM and/or other therapeutic agent set forth herein may also beused in pharmaceutical kits which comprise one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of the SERM. An effective amount can be determined asan amount that provides some relief from the symptoms to be alleviated.Such kits may further include, if desired, one or more of variouscomponents, such as, for example, containers with the compound,containers with one or more pharmaceutically acceptable carriers,additional containers, and instructions. The instructions may be inprinted or electronic form provided, for example, as inserts or labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components.

EXAMPLES Example 1 Results from Surgeries Performed with and withoutExogenous BMP

This example is directed to demonstrate the efficacy of BMP-2 tostimulate bone fusion in sacroiliac joint procedures.

A series of sacroiliac joint fusion surgeries were performed using anopen procedure to expose the sacroiliac joint. Exogenous BMP treatmentwas introduced at the site of surgery to some patients. The union andnon-union rate of the sacroiliac joint 3 month intervals after thesurgeries were compared. Significant improvement in union rate is shownin surgical cases where exogenous BMP was delivered locally at the siteof the fusion. Specifically, BMP-2 (Infuse™ from Medtronic) was placedinto the site in association with a collagen sponge along with a spinalfusion cage and bone graft. The union and non-union frequencies ofsacroiliac joint fusion surgeries performed using the open procedurewith and without exogenous BMP are analyzed and the results are listedin Table 1. Although there are variations in the techniques used in thecases, and most of the with-BMP cases came later in the series, achi-square test of the results has a p<0.00001, indicating statisticallysignificant difference in the rate of fusion between the with andwithout BMP groups.

TABLE 1 Sacroiliac Fusion Cases Union Non-Union with-BMP 70 1 withoutBMP 45 18

The influence of BMP on the outcome of the surgeries was furtheranalyzed in different patient sub-groups. As shown in FIG. 2 (a), whilenon-smokers responded favorably for the use of BMP, the effect is morepronounced for smokers. In fact, the use of BMP has filled the fusionrate gap between the smokers and non-smokers. When BMP was not used, thefusion rate of smokers is significantly (about 20%) lower than thenon-smokers, which is expected given the known adverse effect of tobaccosmoking on bone healing. When BMP is used, however, both the smoker andnon-smoker appear to have fusion rate of >90%. FIG. 2 (b) shows theeffect of BMP usage on female and male patients. When BMP was not used,the fusion rate of male patients is significantly (about 25%) higherthan the female patients. When BMP is used, the gap between the fusionrate of male and female patient shrank to less than 10% and both patientgroup appear to have fusion rate of 90% or greater.

Example 2 Bone Morphogenetic Protein Alone for Bone Fusion

This example is directed to results of sacroiliac joint fusion in postmenopausal women using exogenous BMP-2 administered at the joint.

Joint fusion surgeries were performed either using an open procedureexposing the joint, as described in Example 1, or using a less invasiveprocedure similar to the procedures described in U.S. Patent ApplicationNo. 2009/0024174 to Stark et al, entitled: “Bone screws and particularapplications to sacroiliac joint fusion”, incorporated herein byreference. With either procedure, a spinal fusion cage was inserted tofuse the joint, and BMP-2 (Infuse™) was placed in the joint with acollagen sponge. The results with the open and closed procedure werecomparable. Some of the patients involved in this study were female atage of over 60 years old. Exogenous BMP-2 was dosed at the time ofsurgery around the graft. The bone healing was examined by computerizedtomography three months after surgery and the results are shown in FIG.3, where the compromised incorporation of bone grafts in postmenopausalfemales are visible. In FIG. 3( a), there exist a significant gap 104between the bone graft 102 and the host bone. In FIG. 3( b), asignificant gap 108 is shown to be between the bone graft 106 and thehost bone. The localized administration of bone morphogenetic protein tofacilitate joint fusion/immobilization therefore appears to beinsufficient for some patients, especially postmenopausal women.

FIG. 4 shows various perspective computerized tomography images of hostbone with graft of a healthy 30 year old male, three months after thesurgery. The male patient, although having a normal healthy recovery,the bone graft does not show similar maturity and healing of the 60+year old postmenopausal woman who received both local BMP-2 and oralraloxifene, as discussed in Example 3 below. Raloxifene thus seems tohave potentiated healing processes that is better than normal healing.

Example 3 The Effect of Raloxifene on Bone Healing

This example demonstrates the effectiveness of raloxifene to improve theeffectiveness of sacroiliac joint fusion in postmenopausal women.

Joint fusion surgeries were performed using a less invasive proceduresimilar to the procedures described in U.S. Patent Application No.2009/0024174 to Stark et al, entitled: “Bone screws and particularapplications to sacroiliac joint fusion”, incorporated herein byreference. The patients involved in the study were female at age of over60 years old. Raloxifene (60 mg/day) was administered orally to somefemale patients after bone fusion surgery for three months. During thebone fusion surgery, a spinal cage was inserted to fuse the joint andBMP-2 associated with a collagen sponge (Infuse™) was placed into thesite during the procedure. Exogenous BMP-2 was dosed at the time ofsurgery around the graft both in control and in raloxifene treatedpatients. Significant improvement in bone healing is observed inraloxifene treated patients. Referring to FIG. 3, computerizedtomography images of the host bone in a raloxifene treated patient fromtwo perspectives are shown. The three month old graft 112 appears to befully healed and incorporated into the host bone. The healed boneportion 114 has “ground glass” mature bone appearance, which isdifficult to achieve anywhere in the bone healing situations, exceptwith the passage of long periods of time. It is all the more evidentwithin the implant, because the graft is relatively avascular there,where it is isolated by the implant walls.

These results suggest that the accelerated superior healing of the bonegraft is the result of oral raloxifene administration. The resultsindicate that the combination of therapeutic agents (BMP-2 andraloxifene) result in the combined effects of revascularization, stemcell differentiation, cytokine secretion, cell proliferation, andimportantly, bone turnover, leading to the mature bone appearance andfully incorporated bone graft shown in FIG. 5.

The results from the raloxifene treated patients are further comparedwith patients treated with exogenous BMP-2 only and the results areshown in FIGS. 6 and 7. As shown in FIG. 6, the left image FIG. 6( a)shows X-ray image of the host bone of raloxifene/BMP-2 treated patientshaving fully incorporated bone graft and with the bone took on anoverall mature appearance. The right image FIG. 6( b) is computerizedtomography image of the host bone of a patient treated with exogenousBMP-2 only, showing the bone graft 116 not fully incorporated with gaps118 appear round the bone graft 116. Similarly, for two other patientswho had the bone fusion surgery, the patient who was under treatmentwith raloxifene/BMP-2 shows the incorporated bone graft 122 appears tohave incorporated surrounding 124 and took on a mature bone appearancein FIG. 7( a). In contrast, for the patient who received BMP-2 only,though healing to some degree occurred with BMP without raloxifene asshown in FIG. 7( b), the overall bone healing is not as mature as thepatients in FIG. 7( a) as evident by the lack of maturity within theimplant 122, with problem area 126, where the stress of failedrevascularization and failure of growth is probably greatest.

These results suggest a synergistic effect of raloxifene and exogenousBMP-2. The results obtained for postmenopausal women were observed to bebetter with the combination of raloxifene and BMP-2 than the resultsobtained from a 30 year old male patient who received BMP-2, asdescribed above in Example 2. Therefore, it would be expected thatraloxifene or other suitable SERM would also have beneficial effects forbone fusion if administered to men and to pre-menopausal women.

The bone graft procedures, while done equivalently, because thedifference of with or without oral raloxifene administration, can yieldsignificantly different results. Patients with fully incorporated bonegraft such as those shown in FIG. 5 and FIG. 6( a) may have no painafter the three month treatment period. In contrast, delayed healing,pain, and future surgery may very likely to be necessary for patientswho fail to incorporate the bone graft such as those shown in FIG. 6( b)and FIG. 7.

In some treatment cases, the oral administration of raloxifene isinitiated until sometime after the bone fusion surgeries. The bonehealing or bone graft incorporation in the delayed raloxifeneadministration cases are not as complete as when raloxifene wasadministered immediately following the surgery. When compared withcontrol patients where BMP-2 only is administered, however, somepatients with delayed raloxifene administration seemed to show superiorrecovery results. The improvement effect shown by the delayed raloxifeneadministration may be advantageous in some situations when raloxifenecan not be administered immediately after surgery due to other medicalconcerns.

The embodiments above are intended to be illustrative and not limiting.Additional embodiments are within the claims. In addition, although thepresent invention has been described with reference to particularembodiments, those skilled in the art will recognize that changes can bemade in form and detail without departing from the spirit and scope ofthe invention. Any incorporation by reference of documents above islimited such that no subject matter is incorporated that is contrary tothe explicit disclosure herein. All patents, patent applications, andpublications referenced herein are hereby incorporated by referenceherein to the extent that the incorporated material is not contrary toany of the explicit disclosure herein.

We claim:
 1. A method for the improvement of bone healing, the methodcomprising: administering locally an effective amount of a compositioncomprising a selective estrogen receptor modulator (SERM) to a patient,to improve the bone healing process.
 2. The method of claim 1 whereinthe patient also receives an osteoconductive material.
 3. The method ofclaim 1 wherein the bone healing process comprises administering theeffective amount of composition to a patient that has received animmobilization element interfacing with a joint, to result in jointimmobilization or fusion.
 4. The method of claim 1 further comprisingadministering a bone morphogenetic protein (BMP) to the patient tofacilitate bone healing.
 5. The method of claim 4 wherein the BMP isBMP-2, BMP-7, or a combination thereof.
 6. The method of claim 1 furthercomprising administering a cellular cytokine to the patient tofacilitate bone healing.
 7. The method of claim 1 wherein the SERM isafimoxifene, arzoxifene, bazedoxifene, clomifene, femarelle,lasofoxifene, ormeloxifene, tamoxifen, toremifene, analogs orderivatives thereof, or a combination thereof.
 8. The method of claim 1wherein the SERM is raloxifene, analogs or derivatives thereof, or acombination thereof.
 9. The method of claim 1 further comprisingadministering systemically calcium, vitamin D, or a combination thereofin addition to the SERM to improve bone healing.
 10. The method of claim1 further comprising administering nutritional factors, endocrinefactors, growth factors, synthetic or natural anabolic steroids, or acombination thereof in addition to the SERM to improve bone healing. 11.The method of claim 1 wherein the SERM is administered directly tolocation selected for bone healing.
 12. The method of claim 1 whereinthe SERM is administered to the tissue surrounding the location of bonehealing.
 13. The method of claim 1 wherein the bone healing processcomprises fusion of adjacent vertebrae.
 14. The method of claim 1wherein the bone healing process comprises fusion of the sacroiliacjoint.
 15. The method of claim 1 wherein the patient is apost-menopausal woman.
 16. The method of claim 1 wherein the compositionis controllably released from a suture.
 17. A method for the improvementof bone healing, the method comprising: administering BMP locally to thebone location for healing and administering an effective amount of acomposition comprising a selective estrogen receptor modulator (SERM) toa patient, to improve the bone healing process.
 18. The method of claim17 wherein the SERM is administered directly to the bone healinglocation or surrounding tissue.
 19. The method of claim 17 wherein theSERM is administered systemically.
 20. The method of claim 17 whereinthe SERM is raloxifene, analogs or derivatives thereof, or a combinationthereof.
 21. The method of claim 17 wherein the BMP is BMP-2, BMP-7, ora combination thereof.
 22. The method of claim 17 wherein the bonehealing comprises fracture union by traumatically induced fracturemechanisms, stress fractures, or un-united fractures.
 23. The method ofclaim 17 wherein the fusion or immobilization involves fusion of thesacroiliac joint.
 24. The method of claim 17 wherein the patient is apost-menopausal woman.